The purpose of this RO3 application is to describe the relationship between longitudinal changes in measures of fatness, and serum leptin concentrations, in users and non-users of DMPA, and whether leptin levels are modified by baseline fatness, estradiol concentrations or physical activity. Leptin is believed to act centrally via neurotransmitters in the hypothalamus to regulate energy balance and inhibit adipogenesis. Despite extensive research on the actions of leptin at the cellular level, little is known about the variability of leptin in response to weight loss and gain over time. Identifying the biological contributions of obesity could aid the development and tailoring of new therapies, and may serve to place obesity in a context that removes some of its psychological and social ramifications. Data from our long-term study of bone density in women taking depot medroxyprogresterone acetate (DMNPA), demonstrates a significant increase in fat mass, and changes in site-specific fat mass accumulation, related to DMPA use. Because of the substantial and rapid increase in fat observed in DMPA users, and the variability of fat change in both DMPA users and controls, this population is an excellent model to better understand hormonal mechanisms for fat gain, fat loss and fat maintenance in general, and specifically in conditions of lower estrogen. Furthermore, since leptin secretion is regulated by circulating estrogen levels, leptin may have particular relevance to the DMPA-induced increase in fat mass. We propose to use the unique data set that we have developed during our on-going study of DMPS and bone density, to longitudinally evaluate the relationship between changes in fat mass and changes in serum leptin. This large data set includes stored sera, sophisticated measurements of site-specific far mass, and documentation of physical activity levels. These parameters were collected prior to, and at 3 monthly intervals during the 2-year study in 323 women either on DMPA or control.